Mark Hyman, MD, Director of the Cleveland Clinic Center for Functional Medicine, sits down with Suzanne Goh, MD for an exclusive interview following her Grand Rounds presentation.
The Institute for Functional Medicine (IFM) in collaboration with Cleveland Clinic Center for Functional Medicine is pleased to share lectures from the Grand Rounds presentations. A series featuring pioneers and thought leaders in Functional Medicine.
0:00:00.0 Mark Hyman: Hello everyone, I'm Dr. Mark Hyman here at the Center for Functional Medicine in Cleveland and at Cleveland Clinic, and I'm so happy to have Dr. Suzanne Goh here who's an extraordinary scientist, researcher, clinician, whose pioneering work in autism is really changing our thinking about how to approach these children with this devastating disease that's focused not only on behavioral aspects, but also on the neurobiology and biochemistry and physiology. And looking really more at autism as a metabolic encephalopathy. And it’s really great to have you here in Cleveland, and you just did grand rounds and sort of opened up a doorway to a new way of thinking, which is a major paradigm shift, from refrigerator mothers to a metabolic disorder, which is a very different view. And I'm curious to maybe start off, how did you come as a pediatric neurologist to understand that the old paradigm was broken and that we need a new of thinking that broadens our view of this disorder?
0:01:04.5 Dr. Suzanne Goh: When I look back at my own path and what's supported and enabled the work that we're doing now, I think it very much started from having a view of medicine from the outside initially. So, when I was an undergraduate, my major was the History of Science, which is kind of a unique major.
0:01:27.0 MH: It's like a liberal arts science degree.
0:01:30.3 SG: Yes. And fortunate that it was available and that it allowed for the pre-medical path to be interwoven to that. So that made a big difference, and so I've always had an interest in the medical humanities, which I think have so much to contribute to how we practice medicine. And I also think that I had the opportunity to study... I think Interdisciplinary studies are so important and it really influences the kinds of questions we ask, the research questions, in fact, how we go about research and so, I would say that that was for me, very formative.
0:02:11.9 MH: You had a quote in your lecture from E. O Wilson, who's a social biologist from Harvard, who's written a book called, Consilience: The Unity of Knowledge, which is really about this false architecture of medicine, and that science is general and all knowledge is general, and everything's connected, and that we tend to ignore those connections, and that these artifacts that we have of specialties and diseases, doesn't really make sense, given what we know now in 2017 about the nature of systems thinking and biology. I want to dive into a particular window that you've opened up, which is, the role of mitochondrial dysfunction in autism, and then not only as a sort of a positive factor, but also a doorway to therapy, which is kind of unusual, right?
0:02:58.5 SG: Yes.
0:03:00.0 MH: So how did you come to that? And can you share with us some of the key findings? And then I want to get into how you assess these patients more in detail and then the treatment, because I think everybody who's listening is probably very curious about how you diagnose it, how do you treat it.
0:03:13.1 SG: Right, right. So, probably the first thing worth saying is that mitochondrial dysfunction in autism is heterogeneous, so it's certainly not a single entity. The function of mitochondria is so complex. There are probably best characterized as a metabolic signaling platform. So, the metabolic pathways and processes that they impact are vast. So mitochondrial dysfunction is not one thing. Even for those with autism, there's some research supporting what seems to be a deficiency or reduced function of certain aspects of the mitochondria respiratory chain, but there's also research supporting the idea that there's excessive hyper-function of elements of the respiratory chain in some individuals with autism. And that maybe one sort of mechanism corresponds more to a phenotype of low arousal, low tone, low energy. And the other corresponds...
0:04:10.6 MH: You see a lot of these because of hypotonia, right?
0:04:13.1 SG: Yes. And then in contrast, there's another phenotype of hyperactivity, excess energy, and so it's not yet known, but it's possible that there is sort of a correlation between the mechanism and the phenotype, and that mitochondrial dysfunction is something that can look a lot of different ways. But there are some classic presentations one of which is regression in the first few years of life in the setting of a physiological stressor. There's some very interesting research happening at UCSD in the lab of Dr. Bob Naviaux, looking at what he's termed the “cell danger response,” which is another way in which mitochondrial function can be disturbed, in which the mitochondria are in state of, essentially a stress state, and it leads to a whole cascade of metabolic disturbances for which there may be some therapeutic interventions that are investigational this time.
0:05:05.4 MH: Like the Suramin trial.
0:05:07.2 SG: That's right.
0:05:07.9 MH: Which is, it's an old drug that was used in Africa for infectious disease, right?
0:05:11.9 SG: Right, right.
0:05:12.6 MH: And now, it's being used in autism. You've seen some interesting positive results around it?
0:05:17.1 SG: Yes, just recently, we published the first pilot, a very small randomized controlled trial to look at the safety and tolerability of low-dose Suramin, and the initial results are positive, and plans are in place for a second trial.
0:05:30.7 MH: And the mechanism is around the cell danger response?
0:05:32.9 SG: That's right, Suramin essentially blocks receptors, puranergic receptors on the surface of the cells that are activated by extracellular ATP, so that the cell danger response, a part of it involves the release from cells of ATP. So, we know the ATP inside cells is helpful, ATP outside of cells signals this sort of stressed state and perpetuates the stressed state, which is characterized by increased free radicals and many other metabolic disturbances.
0:06:04.9 MH: So, you see it as an energy deficit in the brain, so that it can't do the normal processing that it should, right?
0:06:12.1 SG: Right. So that's thought to be one of the mechanisms.
0:06:15.6 MH: This is like an acquired mitochondriopathy, it's not necessarily saying they're born with it or that it's an inherited metabolic disorder.
0:06:21.8 SG: Right. In fact, researchers have looked at, in those children with autism who have biochemical evidence for mitochondrial dysfunction, do they have a genetic abnormality to explain it, and the vast majority do not. So, it's thought to be secondary mitochondrial dysfunction rather than primary. Primary being related to gene defect, but the gene defect doesn't seem to be present. So, then it raises the question, well, perhaps mitochondrial disturbance is a downstream consequence of other factors, potentially environmental factors.
0:06:54.1 MH: So environmental toxins.
0:06:56.1 SG: So, exposure to environmental toxins, which as I mentioned in the presentation, we actually know quite a lot about... We know many of the industrial chemicals that have developmental neurotoxicity, and we know that their mechanism of action of many of them is in impacting the function of mitochondria. So that's certainly one pathway that's increasingly well characterized, and there are contributing factors from inflammation and general oxidative stress.
0:07:32.8 MH: It's a vicious cycle. Fascinating though, in the work of functional medicine there's a group of folks that work in the autism space, and the diagnostics we do are pretty on the fringe, we look at stool testing and we'll look at organic acids, we'll look at the oxidative stress markers. We'll look at nutritional status, we often see really extreme abnormalities in these kids, it's like they're... I'm a family doc, so I see babies all the way to 100-year-old people. And it's fascinating to me that of the thousands and thousands of patients that I've seen, the autistic kids are really outliers in terms of the degree of abnormalities, they don't have a little oxidative stress they have a lot, or test ranges in the top 1 or 2%. And do you see that kind of thing where they're just sort of...
0:08:36.2 SG: Yes, we do. I'll say probably one way in which our practice is a little bit different from maybe a functional medicine practitioner is that we, in part because we do such a wide range of therapies, that we don't do the degree of some of these.
0:09:00.6 MH: Diagnostics.
0:09:00.6 SG: Diagnostic tests. Also, because in young children, it's just harder very often to do the test and because we're almost always working in a case of some limitation of resources. And there are some tests that are, especially for young children, there are things to be ruled out neurologically, like sub-clinical seizures, electrical status epilepticus of sleep, and so it's a process. But I would very much like for our practice to be doing more of this over time.
0:09:32.7 MH: Yeah, if finances were not an issue and it was reimbursed, and it was a part of the practice it would be.
0:09:40.1 SG: Yes.
0:09:40.2 MH: So, what are you testing as we look at organic acids that you measure pyruvate, lactate, alanine, those other markers of mitochondrial dysfunction.
0:09:49.7 SG: So, a very routine panel for us would be a CBC, a chem 20, lactate, pyruvate, plasma amino acids, urine organic acids and a carnitine profile. And that's a very good place to start. Others that we would like to test for, if we can get enough blood to do so would be Co-Q10 level, selenium, vitamin E level, others that are part of our very routine initial panels would be thyroid studies, iron, zinc, vitamin D, B12...
0:10:32.5 MH: So, take us through what we would find and then what you'd do for... What were the pearls around organic acids or lactate what are the... For a person listening like how do I apply this.
0:10:44.3 SG: Sure, so some of the patterns that we see most commonly are a mild elevation of lactate in the setting of a blood draw that wasn't traumatic, the tourniquet was released, the samples processed properly, and yet the lactate is elevated just slightly above the normal range, so not a dramatic elevation, but a mild one. A lactate to pyruvate level of greater than 20. An alanine to glycine ratio of 2.5 or greater. Mild elevations of the liver enzymes, mild elevation of ammonia in a sample that was processed properly, acylcarnitine profile with very mild elevations across multiple species, different length chain fatty acids.
0:11:36.5 MH: Or carnitine.
0:11:37.0 SG: Or a low total carnitine level, low Co-Q10. Those are all common findings.
0:11:47.0 MH: So, I understand the elevations in lactate and pyruvate indicating mitochondrial dysfunction. But the, you said ammonia and things like Co-Q10 carnitine those are... The dietary stuff related to Co-Q10 and carnitine, the ammonias, is that related to gut function where is that coming from.
0:12:12.2 SG: Well, classically, we think of these mild elevations in ammonia as being related to liver dysfunction and as well as the elevated transaminases.
0:12:21.5 MH: That's when we check in hepatic encephalopathy, right?
0:12:25.2 SG: And elevations of ammonia may point to urea cycle disorders if it's higher, but more mild elevations are likely pointing to mitochondrial dysfunction. In the urine organic acids, mild elevations of Kreb cycle intermediates are also another sign, and you're right that there can be multiple sources. So, abnormalities in a single analyte could be for multiple different causes, but it really is the overall pattern that's suggestive.
0:12:58.5 MH: Yeah, so you're looking for mild deviations from normal to indicate some subtle metabolic derangement.
0:13:05.6 SG: And in the setting of a suggestive clinical history, it really warrants some therapy, which can also be informed by the test findings. So, a mitochondrial cocktail that we commonly use is one that includes L-carnitine, especially if carnitine levels are low, Co-enzyme q10, B complex vitamins, vitamin c and vitamin e. So that is a very common starting cocktail for us.
0:13:36.8 MH: And so, when you apply these therapies, what do you seeing in these kids? Because you treat a whole range and more extreme cases.
0:13:43.3 SG: Yes, so a wide range of changes. There can be improvements in attention, awareness, self-regulation, those very often occur early in treatment. A reduction of repetitive and obsessive-compulsive types of behaviors, increase in language. More interest and awareness of social interaction and engagement in social interactions.
0:14:18.2 MH: You ever think kids just wake up and... Or is it when you combine all the therapies together like the diet and the treatment.
0:14:25.7 SG: There's a whole range, and for the most part, the improvement is one that's gradual, ess so maybe an awakening, but more one of gradual and increasing developmental progress, across many different areas.
0:14:50.2 MH: Fascinating. So, one of the things we often think about in functional medicine is upstream causes. So, mitochondrila function could be primary, but it's mostly secondary as you mentioned. So, the question is, how do you go up the chain, because you can give them mitochondrial support, but unless you deal with the drivers, which is environmental toxins, sources of inflammation and oxidative stress, what do you think can deal with that.
0:15:22.1 SG: I think the best approach is to really target the upstream causative factors, as well as the downstream impairment. And so, nutritional supplements are helpful, but most helpful when in the context of different nutritional and lifestyle modifications. So, there are stressors in the home environment, both related to exposures, so environmental type of stressors, pesticide in foods or, something like EMF, or a variety of factors in the home that may be increasing the burden or the load on a child's metabolism. Because so much of what we do is in the behavioral therapeutic side, we also know there are a whole host of stressors involved in relationships and social interactions that can also be diminished, which has benefit for metabolism, so the link...
0:16:22.7 MH: There's different doorways it can take.
0:16:24.7 SG: Yes.
0:16:24.7 MH: Yeah, it's fascinating. The things that we find that are common factors in autism that, I think you're probably seeing as well, severe gut dysfunction as a source of inflammation, obviously the stress, food reactions, gluten, dairy, we could get fungal overgrowth, which is like really an outlier in medicine as some weird thing that we do, but in action we find it extreme... I mean in terms of intervention antifungals are powerful for these kids, heavy metals, and then his home methylation, sulfation cycle of disruption. Do you find the same things in these kids?
0:17:06.6 SG: We do. I would say a lot depends on the age and the unique presentation of the child, and we go about trying to prioritize and really target potentially the highest yield symptoms.
0:17:40.6 MH: You go for 80, 20 on it?
0:17:42.4 SG: Yeah, we try to do that, and also are guided by the tests and interventions that at least in our field have the most research to support them. So, it's always a balance. And as we get through some of those early ones, then we can look in a little bit more detail at some of the other areas that are also hugely important, a little bit outside of my expertise, but which I've made efforts to become educated in. And so, one of them is, conventionally, neurologists don't do a lot of treatment for the gut.
0:18:23.6 MH: No, but that's down there. We're above all that literally and figuratively.
0:18:26.4 SG: Yes, that's why the body fluid we’re most comfortable with is cerebral spinal fluid!
0:18:33.4 MH: Yeah, exactly right.
0:18:36.5 SG: But we do, in our clinic, a lot of interventions that target gut health. And in fact, when we see in a child who's been progressing well and we see agitation or dysregulation or an increase in repetitive behaviors, our staff, all our staff, even our behavior therapists, our occupational therapists, and others, immediately think the gut. And so then as a team we talk with the parents, we find out what's been happening, what the child's been eating, what their bowel movements have been like. What supplements are they on, are they on the things that may help, or have they recently stopped their digestive enzymes and now symptoms have emerged, and so it's very much integrated into what we do, and I will say our approach has tended to be more symptom driven, and...
0:19:35.9 MH: So, what would you do for gut treatments, for example, in these kids?
0:19:41.0 SG: We use a lot of prebiotics and probiotics. What we're able to give in terms of probiotics has probably less to do with the diversity of the healthy gut and more to do with what sort of species are able to be packaged and taken. So, there's some interesting research that I've been following by Jim Adams at Arizona State University, where it seems that autism is highly associated with a reduction of gut microbiome diversity, and that because the gut has probably close to a thousand different species of bacteria, what we're able to do with probiotics is...
0:20:28.9 MH: A drop in the bucket.
0:20:30.4 SG: Yeah, it's relatively small.
0:20:31.8 MH: We're doing fecal transplants.
0:20:33.3 SG: Yes, where it's in a sense sort of super probiotic where they're able to transplant close to a thousand species rather than just five or ten they get in a probiotic.
0:20:46.5 MH: What are they seeing with those fecal transplant surgeries?
0:20:49.6 SG: The study that was published this year showed improvement. It was a eight-week course of therapy, so improvement in autism symptoms and GI symptoms during that period, and also two months following that, the end of treatment. And I've heard that there's some long-term data about to be published as well.
0:21:08.5 MH: Like mild improvements, or a dramatic improvement?
0:21:12.2 SG: Some with mild and some with dramatic, so sort of a range.
0:21:16.0 MH: Yeah, that's some very crazy therapy for autism, like fecal transplants. But if you're targeting some ideologies, because then that's gonna have downstream effects on mitochondria, active stress, inflammation...
0:21:25.5 SG: Right. So, it sounds unusual, but when you actually look at the mechanisms, there's a lot of rationale to it.
0:21:31.2 MH: So, there's a microbiome mitochondrial connection?
0:21:34.3 SG: Yes, for sure. Everything's interconnected, within the body and outside of the body.
0:21:39.3 MH: Exactly. Amazing. And then how about the toxic load that these kids have... Other than reducing exposure through organic food and stuff, how do you deal with that, do you check for heavy metals, do you check...
0:21:50.9 SG: We are testing for heavy metals, primarily for lead. But our approach is largely about trying to gently enhance the body's own mechanisms for detoxification through steps to increase glutathione. So, we use a lot of N-acetyl cysteine.
0:22:08.8 MH: Yeah.
0:22:10.9 SG: A lot of antioxidants. That's been our primary mode of therapy.
0:22:17.2 MH: Yeah. I mean, I'm a “n of one” practitioner, but I think it's a shared experience among us doing this, that if you test for heavy metals in these kids, that they're often just loaded with mercury and lead on a challenge test, which you wouldn't see in a blood test because they often really hold on to these because they aren't able to mobilize them because of the low glutathione levels and also the stress. It's really, if I had, three things to take with me to a deserted island for autism would be, gluten and dairy-free diet, anti-fungals, and heavy metal treatment.
0:22:51.9 SG: Do you do challenge protocols here?
0:22:54.3 MH: We do, yeah, we do, and we see it. Across the spectrum of, neurologic diseases, we have a whole cohort of special forces soldiers here who are heavily exposed to blast training, they have indoor blast rooms where they blow things up and they shoot things, and they have extraordinarily high levels of lead and metals. And it's fascinating how they, I saw a little girl with autism a couple of days, and her post-challenge level was 42, which was pretty high after I gave her a challenge. And I question like, where did she get all that. She wasn't eating paint chips and running behind cars in Cuba inhaling gas and... So, and it's fascinating to see, and those are... I think, like you said, those are really significant mitochondrial disruptors.
0:23:55.0 SG: Yeah, right, right.
0:23:58.6 MH: And, you wonder, the regulation of antioxidant enzymes, because antioxidants we can take are a drop in the bucket compared to our own endogenous systems of catalase, Superoxide dismutase and Glutathione peroxidase, and other inherent antioxidant enzymes, they're part of mitochondrial protective mechanisms. How do you up regulate those? Do you have any experience or thought about that?
0:24:26.3 SG: I would just say that, and there's a slide I have, I sometimes include in my presentations, which is, I show the two-dimensional representation of all the biochemical pathways in the body, and it's extremely complicated...
0:24:42.4 MH: Mind blowing. [chuckle]
0:24:44.8 SG: And of course, it's an over-simplification.
0:24:48.0 MH: And it's not linear...
0:24:49.8 SG: That's right.
0:24:50.8 MH: Like it's a soup.
0:24:51.7 SG: Right. And so, does it make a lot of sense to work on a single pathway, sometimes, and sometimes it's very helpful. But the things that influence and shift that whole complex soup are what we eat, and how we live, and our quality of sleep, and the quality of our relationships.
0:25:16.6 MH: This is great, it's amazing. And your work, is obviously focused on far more than the biological aspects, you know every doorway into these kids brains through music and other sort of modalities that allow them to re-pattern what's happening.
0:25:33.0 SG: I like to say the brain, especially the developing brain, can be influenced in so many ways, and that's an opportunity. It makes our work harder, and there is a real tendency in medicine these days to specialize because it makes something very unwieldy more manageable, but I think it doesn't do a service to our patients.
0:25:54.4 MH: Well, it doesn't represent reality either, of how our bodies are designed or organized.
0:25:57.8 SG: Yes. And so, I think it's important to create opportunities, and to encourage trainees to be broad and to remain broad, and that's, I know a part of functional medicine, which is to say, it's a way of looking at a whole host of diseases that conventionally are thought of as, oh that's not an autoimmune disease, that's neurological disease, that's a... And it's not actually that way.
0:26:25.5 MH: No, it's not. And what's fascinating is when you look at sort of extremes, for example, autism and Alzheimer's. It's astounding how similar the patterns are in these. And we look at it sort of a subset of snips, like we look at the file snips, methylation snips and so forth, and you see that they share these, and then you see that they all have high levels of inflammation and oxidative stress and toxic load, and often the same therapy as you're using. Like the mitochondrial therapy is for neurogenesis disease, and then anti-inflammatory therapies, and diet, and it's just... That's even being used in ketogenic diets for autism and Alzheimer's, as intervention, so it's like... I think we're pretty much really, in a new era of medicine, we are, you're a pioneer in that, and we're looking at remapping our view of one of the most frightening and burdensome diseases that exist that destroys families and burden our whole healthcare system for the life of these children. We all have an opportunity to start to reverse and stop these conditions, it's just amazing. So, thank you for your work, and for joining us today in Cleveland.
0:27:48.2 SG: Thank you.
0:27:49.5 MH: And thank you everybody for watching. And hopefully, we'll continue this conversation.
0:27:53.3 SG: I hope so. Thank you so much.